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  • Title: The tumour necrosis factor-alpha-mediated suppression of the CCAAT/enhancer binding protein-alpha gene transcription in hepatocytes involves inhibition of autoregulation.
    Author: Foka P, Singh NN, Salter RC, Ramji DP.
    Journal: Int J Biochem Cell Biol; 2009 May; 41(5):1189-97. PubMed ID: 19027873.
    Abstract:
    Tumour necrosis factor-alpha (TNF-alpha) is a key regulator of the immune and inflammatory responses along with numerous other cellular changes during physiological and pathophysiological conditions. The cellular actions of TNF-alpha are associated with both the activation and the inhibition of gene transcription. In contrast to gene activation, the mechanisms underlying the TNF-alpha-mediated transcriptional inhibition remain largely unclear. We have investigated this aspect using the transcription factor CCAAT/enhancer binding protein-alpha (C/EBPalpha) as a model gene. TNF-alpha decreased the expression of C/EBPalpha mRNA and protein in the human hepatoma Hep3B cell line. The activity of the proximal promoter of both the human and the Xenopus C/EBPalpha genes in transfected Hep3B cells was inhibited by TNF-alpha. Transient transfection assays using various Xenopus C/EBPalpha promoter-luciferase DNA constructs showed that a C/EBP recognition sequence was essential for the TNF-alpha response. Electrophoretic mobility shift assays showed that C/EBPalpha bound to this site and co-transfection assays revealed that it was a major activator of the promoter and its transactivation potential was reduced by TNF-alpha. The potential role of nuclear factor kappaB (NF-kappaB) in the response was also investigated in the light of its pivotal role in TNF-alpha signalling. Inhibition of NF-kappaB using pharmacological agents or by transfection of a plasmid specifying for a superrepressor attenuated the TNF-alpha-inhibited C/EBPalpha promoter activity. In addition, an involvement of NF-kappaB in DNA-protein interactions at the C/EBP recognition sequence was identified.
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